Targeting Resistance

Wrestling with cancer can be frustrating. Despite the progress in developing therapies that can effectively control tumor growth, the devil almost always strikes back with resistance. Even for the recent excitement in using immunotherapy to achieve unprecedented success in some cancer patients, resistance has been seen in clinical settings and is under active investigation (Restifo et al., 2016). How dowe tackle resistance to cancer therapy?One effective approach is to nail the culprit—pinpointing the cell population intrinsically insensitive to the treatment and targeting their vulnerability. Recent work from Tessa L. Holyoake and her team successfully applied this strategy on chronic myeloid leukemia (CML; Abraham et al., 2016). CML is characterized by the aberrant activation of ABL1 tyrosine kinase due to chromosome translocation, and tyrosine kinase inhibitors (TKIs) have been the standard treatment with clinical efficacy. However, patients with CML eventually relapse because the survival of leukemic stem cells (LSCs) does not rely on the elevated kinase activity and therefore cannot be eradicated by TKIs. Through integrated analyses, the team exposed the essential role of p53 and c-MYC on the CML network and an addictive dependency of LSCs on these two signaling hubs. They further showed that a combinatory treatment targeting p53 and c-MYC could effectively kill LSCs, raising the hope of using this approach for treating CML patients relapsing from TKIs (Abraham et al., 2016). Leukemia is not the only type of cancer in which targeting intrinsic resistance from a specific population is starting to show promise. Indeed, by developing a mouse model with knockin reporters, Tannishtha Reya and colleagues were able to identify high expression of the stem cell determinant Musashi (Msi) as a marker for populations in pancreatic cancer with strong tumor-initiating capacity and conferring drug resistance. Inhibiting Msi significantly changed the trajectory of disease progression and almost doubled the survival time in mouse models. Moreover, simultaneously inhibiting two of